Pharmaceutical compositions and methods of controlling cardiac arrhythmias with n-substituted phthalimide compounds



United States Patent PHARMACEUTICAL COMPOSITIONS AND METH- ODS OFCONTROLLING CARDIAC ARRHYTH- MIAS WITH N-SUBSTITUTED PHTHALIMIDECOMPOUNDS Grover C. Helsley, Richmond, Va., assignor to A. H.

Robins Company, Incorporated, Richmond, Va., a corporation of VirginiaNo Drawing. Original application Oct. 6, 1965, Ser. No. 494,304, nowPatent No. 3,316,276, dated Apr. 25, 1967. Divided and this applicationDec. 23, 1966, Ser. No. 605,150

U.S. Cl. 424-274 8 Claims Int. Cl. A61 27/00; C07d 27/52 ABSTRACT OF THEDISCLOSURE N-substituted phthalimide compounds, compositions, andmethods are disclosed which have been shown to have antiarrhythmicactivity in standard laboratory animals. Arrhythmia were produced bymechanical and chemical means and normal sinus rhythm was restored byadministering compounds of the present invention.

This invention relates to a series of novel N-substituted phthalimidecompounds, particularly N-(substituted-3- pyrrolidinyl)phthalimides,therapeutic compositions containing the same as active ingredients andmethods of making and therapeutically administering said compounds andcompositions.

The present application is a division of my prior-filed copendingapplication Ser. No. 494,304, filed Oct. 6, 1965 now Patent No.3,316,276.

The novel compounds described hereinafter have utility asphysiologically active agents and particularly as effectiveantiarrhythmic agents, therapeutically applicable in the treatment ofcardiac arrhythmias.

It is accordingly an object of the present invention to provide novelcompounds which have a high degree of antiarrhythmic activity. Anadditional object is the provision of compounds having antiarrhythmicactivity and which produce minimal side effects. Another object is toprovide certain novel N (substituted 3 pyrrolidinyl) phthalimides. Afurther object is to provide a method of using said antiarrhythmicagents in the treatment of living animal and especially mammalianbodies. A still further object is to provide pharmaceutical compositionswhich embody the said agents. A still further object is to provide amethod for preparing said novel N-(su-bstituted-3-pyrrolidinyl)phthalimides. Additional objects will be apparent to oneskilled in the art and still other objects will become apparenthereinafter.

The novel chemical compounds of this invention are represented by thefollowing structure formula:

0 II c I j nx)...

3,429,968 Patented Feb. 25, 1969 wherein R is a member of the groupconsisting of hydrogen, lower alkyl, aryl, aralkyl and alicyclyl; R is amember of the group consisting of hydrogen and lower alkyl; R" is amember of the group consisting of hydrogen, halogen having an atomicweight less than 80, trifluoromethyl, lower alkyl and lower alkoxy; m is02 and n is 0-4.

The terms lower alkyl and lower alkoxy as used herein include straightand branched chain radicals of from 1 to 4 carbon atoms inclusive.

Examples of lower alkyl radicals are methyl, ethyl, propyl, N-butyl,isopropyl, isobutyl and tertiary butyl. Suitable lower alkoxy radicalsare methoxy, ethoxy, propoxy, isopropoxy, and butoxy. Aryl radicalsinclude the unsubstituted phenyl radical and phenyl radicals substitutedby any radical or radicals which are not reactive or otherwiseinterfering under the conditions of the reaction, such as nitro, loweralkyl, trifluoromethyl, halo, and the like. Included in the term aralkylare lower-alkyl substituted monocarbocyclic aryl groups such as benzyl,phenethyl, methylbenzyl, phenpropyl, and the like. Alicyclic radicalsinclude such groups as cyclobutyl, cyclohexyl, cyclopentyl,ethylcyclopentyl, and cycloheptyl.

This invention also includes pharmaceutically acceptable acid additionsalts of the above defined bases formed with non-toxic organic andinorganic acids. Such salts are easily prepared by methods known to theart. The base is reacted with either the calculated amount of organic orinorganic acid in aqueous miscible solvent, such as ethanol orisopropanol, with isolation of the salt by concentration and cooling oran excess of the acid in aqueous immiscible solvent, such as ethyl etheror isopropyl ether, with the desired salt separating directly. Exemplaryof such organic salts are those with maleic, fumaric, benzoic, ascorbic,pamoic, succinic methanesulfonic, acetic, propionic, tartaric, citric,lactic, malic, citraconic, itaconic, p-aminobenzoic, glutamic, stearicand the like. Exemplary of such inorganic salts are those withhydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitricacids.

In addition this invention includes pharmaceutically acceptable,nontoxic quaternary ammonium salts of the above defined bases. Thequaternary ammonium salts are readily formed by treatment of thecorresponding free base with the appropriate salt-forming substance,including, for example, methyl chloride, methyl bromide, methyl iodide,methyl sulfate, ethyl chloride, ethyl bromide, ethyl iodide, n-propylchloride, n-propyl bromide, n-propyl iodide, isopropyl iodide, n-butylchloride, n-butyl bromide, isobutyl bromide, sec butyl bromide, n-amylchloride, isoamyl chloride, n-amyl bromide, isoamyl bromide, n-amyliodide, isoamyl iodide, n-hexyl chloride, isohexyl chloride, n-hexylbromide, isohexyl bromide, n-hexyl iodide, isohexyl iodide, or similarquaternary salt-forming substances, according to general procedureswhich are well known in the art.

It will be readily apparent to one skilled in the art that certaincompounds of this invention may be present as optical isomers. Theconnotation of the general formulas presented herein is to include allisomers, the separated d and l isomers as well as the dl mixtures ofthese isomers.

In general, the novel compounds of this invention are prepared byreacting a selected B-halopyrrolidine substituted at one or morepositions with a lower :alkyl radical or a selected 3-pyrrolidinyltosylate substituted at one or more positions on the pyrrolidine nucleuswith a lower alkyl radical with an appropriately substituted phthalim-Wherein R, R and R" have the same meaning ascribed to them above, M ispreferably sodium or potassium and Y is preferably halogen orarylsulfonate.

In the preferred method of preparing the present compounds, the reactionmaterials and conditions for the above identified reactions aregenerally as follows:

The 3-halopyrrolidines substituted at one or more positions with a loweralkyl radical or the 3-pyrrolidinyl arylsulfonates substituted at one ormore positions on the pyrrolidine nucleus with a lower alkyl radicalused as starting materials for the preparation of the newN-(substituted-3-pyrrolidinyl)phthalimides of the present invention canbe prepared in accordance with the methods described in Synthesis andAnticholinergic Activity of Ester Derivatives of Substituted3-Pyrrolidinols by Ryan and Ainsworth, J. Org. Chem. 27, 2901 (1962),4-(fi-Substituted Ethyl)-3,3-Diphenyl-2-Pyrrolidinones, A New Series ofCNS Stimulants by Lunsford et al., J. Med. Chem. 7, 302 (1964) and inUS. patent application Ser. No. 422,- 570, filed Dec. 31, 1964, by CarlD. Lunsford and Albert D. Cale, Jr., entitled Heterocyclic OrganicCompounds, Intermediates Therefor and Products and Use Thereof, all ofwhich publications are hereby incorporated by reference as if fully setout herein.

The compounds of the present invention are prepared by dissolving thesubstituted 3-halopyrrolidine or the substituted 3-pyrrolidinylarylsulfonate in and suspending the metalated substituted phthalimide ina suitable solvent such as dimethyl sulfoxide, methanol, ethanol,benzene, toluene, and the like, which will not enter into the reaction,but which will provide a reaction medium. The amount of solvent usedwill depend to a certain extent upon the equipment used. Generallyspeaking, however, about 5 parts of solvent per part of the phthalimideand about 1 to 2 parts of solvent per part of the pyrrolidine compoundare used.

The reactants, dissolved and suspended as described above, are thenadmixed by treating dropwise over a period of about 30 minutes thestirred metalated phthalimide suspension at 65-115 C. with the desiredpyrrolidine compound. In an alternative method the reactants and solventare mixed together at room temperature.

The resulting reaction mixture is stirred for a period of time necessaryto effect the formation of the N-substituted phthalimide, usually about16 hours. There is no criticality about the temperature of the reactionmixture but 110115 C. is the preferred reaction temperature.

Isolation and purification of the compounds of the present invention isbest achieved by stripping the reaction mixture of solvent anddistilling the residual oily material or precipitating the crude productby diluting the cooled reaction mixture with a large excess of water andpurifying the compounds from a suitable solvent. Product work-up byother procedures is also feasible in accordance with presently availableinformation and such other methods are equally within the purview ofthis invention insofar as they embody the novel methods hereindisclosed.

The activity of the pharmacologically active agents of the presentinvention, as evidenced by tests in mammals is indicative of theirusefulness for veterinary purposes, and of similar utility in humanbeings as well. It will be, however, clearly understood that thedistribution and marketing of any compound or composition falling withinthe scope of the present invention for use in human beings will, ofcourse, be subject to prior approval by the U.S. Food and DrugAdministration.

The invention is illustrated by the following examples which, it is tobe understood, are merely illustrative and should not be taken in alimiting sense.

EXAMPLE 1 N-( 1-cyclohexyl-3-pyrrolidinyl)phthalimide To a rapidlystirred suspension of 185 g. (1.0 mole) of potassium phthalimide in 1000ml. of dimethyl sulfoxide at C. was added slowly 188 g. (1.0 mole) of3-chlorol-cyclohexyl pyrrolidine. The mixture was heated with stirringfor 16 hours at 112115 C. and then filtered while hot to remove theinorganic salt. The crystalline product which separated from the cooledfiltrate was collected and dried under vacuum. After crystallizationfrom an iso-octane-benzene mixture the dried product weighed 151 g. (51%yield) and melted at 112.5114 C. The analytical sample melted at 113114C. after it -was recrystallized from the same solvent system.

Analysis.-Calculated for C H N O C, 72.45; H, 7.43; N, 9.39. Found: C,72.53; H, 7.33; N, 9.44.

N (1-cyclohexyl-3-pyrrolidinyl)phthalimide ethiodide was prepared in 59%yield and melted at 186-1875 C. after several recrystallizations fromisopropanol-isopropyl ether.

Analysis.-Calculated for C H IN O C, 48.01; H, 5.29; N, 7.00. Found: C,47.75; H, 5.57; N, 7.22.

The maleate salt was prepared using isopropanol as a solvent and meltedat 167-1685 C.

The hydrochloride salt was prepared using isopropanolisopropyl ether assolvents and melted at 191194 C.

Pharmacology.A male mongrel dog (wt. 9.4 kg.) was anesthetized withintravenous phenobarbital sodium, the thorax was opened between thethird and fourth ribs on the right side and the animal artificiallyrespired with 21 Palmer pump. The Grass polygraph and accessoryequipment were used for recording carotid arterial blood pressure,jugular venous blood pressure, the'electrocardiogram, respiration,intestinal motility, activity of the urinary bladder and urinary flow.The pericardium was opened and arranged to form a cradle in which theheart rested. Aconitine (0.25 mg.) was injected into the wall of theright atrium. After an arrythmia (usually a 2:1 rhythm with aventricular rate of at least 200 beats/minute) had been established andpersisted for 20 minutes, an aqueous solution of N (1 cyclohexyl 3pyrrolidinyl) phthalimide (conc. 9.4 mg./ml.) containing 1 equivalent ofhydrochloric acid was given by infusion through the femoral vein at aconstant rate of 1 ml./min. Normal sinus rhythm was restored after adose of 2 mg./ kg. (18.8 mg.) had been given. In the same dog a dose of20 mg./ kg. (198 mg.) of the known antiarrhythmic agent Pronestyl failedto cause reversion of aconitine-induced arrhythmia to a normal sinusrhythm.

In a general pharmacodynamic study the most pronounced effect ofN-(1-cyclohexyl-3-pyrrolidinyl)phthalimide was a relatively transientlowering of the blood pressure.

EXAMPLE 2 N-( l-ethyl-3-pyrrolidinyl)phthalimide3-chloro-l-ethylpyrrolidine (264 g.; 2.0 moles) in 250 ml. of dimethylsulfoxide was added slowly to a rapidly stirred suspension of 370 g.(2.0 moles) of potassium phthalimide in 1500 ml. of dimethyl sulfoxideat 90 C. The reaction mixture was stirred for 16 hours at 110- 115 C.and then the solvent was distilled out of the reaction mixture atreduced pressure. The residue was distilled in vacuo and the fractiondistilling at 143-145 C./ 0.02 mm. was collected separately. Thedistillate which crystallized on standing weighed 284 g. (58% yield) andmelted at 105-109 C. Several recrystallizations from isooctane raisedthe melting point to 110112 C.

Analysis.-Calculated for C H N O C, 68.63; H, 6.60; N, 11.47. Found: C,69.11; H, 6.56; N, 11.30.

Pharmacology.A male mongrel dog (10.1 kg.) was anesthetized withintravenous phenobarbital sodium, the thorax was opened between thethird and fourth ribs on the right side and the animal artificiallyrespired with a Palmer pump. The necessary equipment as described inExample 1 to obtain a complete pharmacodynamic profile was used. Thepericardium was opened and arranged to form a cradle in which the heartrested. Injection of 0.25 mg. of aconitine into the wall of the rightatrium produced an arrhythmia (2:1 rhythm with ventricular rate of 200beats/minute). After the arrhythmia had been established for 20 minutesan aqueous solution of N-(1-ethyl-3-pyrro1idinyl)phthalimide (conc. 10.1mg./ ml.) containing 1 equivalent of hydrochloric acid was administeredby infusion through the femoral vein at a constant rate of 1 mL/min.Three aconitine induced arrhythmias were restored to normal sinus rhythmafter doses of 2.3 -mg./kg. (23.23 mg.), 1.3 mg./kg. (13.13 mg.) and 1.5mg./kg. (15.15 mg.) respectively. Pronestyl also restored the normalsinus rhythm but mg./ kg. (101 mg.) was necessary.

A male mongrel dog (wt. 12.8 kg.) was prepared as in the precedingparagraph and an arrhythmia produced by crushing an area in the regionof the sinoatrial node and then stimulating the area electrically.Normal sinus rhythm was restored when a total of 3 mg./kg. (38.4 mg.) ofN-(1-ethyl-3-pyrrolidinyl)phthalimide had been infused through thefemoral vein.

EXAMPLE 3 N-( l-methyl-3 pyrrolidinyl) -phthalirnide To a rapidlystirred suspension of 139 g. (0.075 mole) of potassium phthalimide in400 ml. of dimethyl sulfoxide at 90 C. was added dropwise 90 g. (0.075mole) of 3- chloro-l-methylpyrrolidine. The mixture was heated withstirring for 16 hours, cooled, and filtered to remove the inorganicsalt. The solvent was evaporated and 18 g. of the residual oil (133 g.)was distilled at reduced pressure. The fraction boiling at 116-118 C./0.02 mm. was collected. The product which crystallized on standing wasrecrystallized several times from isooctane. The white compound meltedat 9295 C. and weighed 7.0 g. (29% yield). The analytically pure samplemelted at 94.595.5 C. after crystallization from isopropyl ether.

Analysis.Calculated for C H N O C, 67.81; H, 6.13; N, 12.17. Found: C,67.54; H, 6.06; N, 12.19.

EXAMPLE 4 N-( 1-iso pro pyl-3 -pyrrolidinyl) phthalimide A rapidlystirred mixture of 118 g. (0.80 mole) of 3-chloro-l-isopropylpyrrolidine, 148 g. (0.80 mole) of potassiumphthalimide and 700 ml. of dimethyl sulfoxide was heated at 110-113" C.for 16 hours and filtered while hot to remove the inorganic salt. Thecrystalline product which formed when the dark red solution was cooledand treated with ca. 100 ml. of water was collected and washed with coldwater. The off-white crystalline product weighed 105 g. (51% yield) andmelted at 130134 C. Several recrystallizations from isooctanebenzenegave colorless material melting at 134135.5 C.

Analysis.-Calculated for C H N 'O C, 69.74; H, 7.02; N, 10.85. Found: C,69.59; H, 7.07; N, 10.74.

6 EXAMPLE 5 N-( 1-phenyl-3-pyrrolidinyl) phthalimide A stirred mixtureof 190 g. (0.60 mole) of 1-phenyl-3- pyrrolidinyl tosylate and 111 g.(0.60 mole) of potassium phthalimide in 1000 ml. of dimethyl sulfoxidewas heated at 65 C. for 7 hours. The material which separated from thecooled reaction mixture was collected, washed with 50% dimethylsulfoxide-water and then with water. A second crop was obtained onfurther dilution of the filtrate with water and was purified byrecrystallization from benzene-petroleum ether (3060 C.). The purematerial melted at 151-153 C.; yield, 97.7 g. (55% Analysis.Calculatedfor C H N O C, 73.95; H, 5.52; N, 9.58. Found: C, 73.91; H, 5.45; N,9.66.

EXAMPLE 6 N-( 1-benzyl-3 -pyrrolidinyl) phthalimide To a rapidly stirredsuspension of 288 g. (1.23 moles) of potassium phthalimide in 800 m1. ofdimethyl sulfoxide at C. was added slowly 240 g. (1.23 mole) of 1-benzyl-3-chloropyrrolidine. The mixture was heated with stirring for 16hours and then filtered hot to remove the inorganic salt. Thecrystalline product which separated from the cooled filtrate wascollected and dried. The white compound weighed 182 g. (48% yield) andmelted at -132 C. Recrystallization from benzene-isooctane raised themelting point to l3l-l32 C.

Analysis.-Calculated for C H N O C, 74.49; H, 5.92; N, 9.15. Found: C,74.51; H, 6.01; N, 9.08.

EXAMPLE 7 N- 1-phenethyl-3 -pyrrolidinyl phthalimide3-chloro-l-phenethylpyrrolidine (258 g., 1.23 moles) was added slowly toa rapidly stirred suspension of potassium phthalimide 288 g., 1.23moles) in dimethyl sulfoxide (800 ml.) while maintaining the temperatureat 90 C. The heated mixture was stirred for 16 hours and then filteredwhile hot to remove the inorganic salt. The product was isolated andpurified in the usual manner.

EXAMPLE 8 4-chloro -N- 1-cyclohexyl-3-pyrrolidinyl phthalimide3-chloro-l-cyclohexylpyrrolidine (188 g., 1.0 mole) was added slowly toa rapidly stirred suspension of potassium 4-chlorophthalimide (219.5 g.,1.0 mole) in dimethyl sulfoxide (1 liter) while maintaining thetemperature at 90 C. The reaction mixture was stirred for 16 hoursmaintaining the temperature at 112115 C. and then filtered while hot toremove the inorganic salt. The product was isolated and purified in theappropriate manner.

EXAMPLE 9 N (1-phenyl-2-met'hy1-3 -pyrrolidiny'l) phthalimide To awell-stirred suspension of 114 g. (0. 665 mole) of potassium phthalimidein 400 ml. of dimethyl sulfoxide was added slowly 97.5 g. (0.665 mole)of vkphenyl-Z- methyl-'3-chloropyrro1idine. The mixture was heated withstirring for 15 hours and filtered while hot to remove the inorganicsalt. The product was isolated by concentrating the filtrate, coolingand adding water to the point of crystallization. The product wascollected and dried.

EXAMPLES '10-"41 By following the principles of the manipulativeprocedures described in the preceding examples and using the alkalimetal salt of appropriately substituted .p'hthalimides and varioussubstituted 3-chloropyrrolidines or 3- pyrrol-idinyl ary l sulfona-testhe following compounds are prepared:

4'trifluorcmethyl-=N-( 1-cyclohexyl-3 -pyrrolidinyl phthalimide 4,5-dimethoxy-N-'( l phenyl-3 -pyrrolidinyl phthalimide 4-meth0xy-N-l-cyclo'hexyl-Ii -pyrrolidinyl)phth-afimide 4-br0m0 N-(l-ethyl-4-methyl-3 -pyrrol-idinyl) phth-alimide 4-bromo-N- (l-ethyl-3-pyrrolidinyl ph-thalimide 4-:bromo-N-( 1-cyclohexyl-3-pyrrolidinyl)phthal-imide 4,5 -di me-thoxy-N- 1-cyclol1exyl-3 -pyrrolidinyl)ph-t-halimide 4,5 -tdimethxy-N-' 1 -cyclohexyl-4methyl-3-pyrrolid-i-nyl)phthalimide 4,5-diethyl-N-'( 1-ethyl 3 -pyrrolidinyl phth'alimide 4,5-dimethyl-N-(l -ethyl 3 -pyrrolidinyl p'hltha'limide 4,5 -diethyl-N-(l-phenyl-3 -'p yrrolidinyl) phth alimide 4,5 -diethyil-'N-'(4-methyl-ll-phenyl-3-pyrnoliclinyl)phthalimide 4, -d-iethoxy-'N- l-phenyl-3-pyrrolidinyl phthal-imide 4,5 -diethoxy-N- 4-met'hyll phenyl3-py-rrolidiny1) phthalimide 4,5 -diethoxy-N-'( l-cyclohexyl-B-pyrnolidinyl)phthalim-ide 4,5 -diethoxy-*N- 1-phene-thyl-3-'pyrrolidinyl phthalimide 4,5 -diethoxy-N-( 1-be-nzyl-3 -pyrrolidinyl)phth-alimide 4,5 -diethoxy-N- 5 me-thyll-phenyl-3 -pyrrolidiny1)phthalimide 4,5 -diethoxy-N 1-isopropyl-3 -pyrroli-dinyl phthalimide4-met'hyl-N-'( 1,2,2-trimethyl 3 -pyrrolidinyl phthalimide 3-met-hyl-N-5 -methyl-'1 -phenyl-3 -pyrrolidinyl) phthalimid-e 3 ,5 -dichloro-N1-benzyl-3 -pyrrolidinyl p'hthalimide 3,4-d-ibromo-N- ('1-benzyl-3-pyrrolidinyl phthalim-ide 3 ,4,5,6 tetrachl0ro-N 0l-methyl-3-rpyrrolidinyl)phthalim-ide 3,4,5 -trichloro-'6-( l-ethy1-3-pyrrolidinyl)phthalimide 3,4,5 -trichloro-N-( 1,2,2-trimethyl-3-pyr-rolidinyl )pht-halimide 3 ,5 -dichloro-N-(1-benzyl2,2-dim'et'hyl-3-pyrrolidinyl) phthalimide 3,4,5-trimethyl-N-1-ethyl-3-pyrrolidinyl)phthalimide 3-ethoxy-N-l-phenethyl-4-methyl-3-pyrrolidinyl) phthalimide 4,5-dibromo-N-1-phenethyl-4,5-dimethyl-3-pyrro1idiny1) phthalimide 3 -triflu orome-thyl N- l -cycl ohexyl-2methyl-3 -pyrrolidinyl phthalimide.

The invention further provides pharmaceutical compositions comprising,as active ingredients, at least one of the compounds according to theinvention in association with a pharmaceutical carrier or excipient. Thecompounds are thus presented in a form suitable tor oral, rectal,parenteral or intracardial administration, or in a form suitable forinhalation. Thus, for example, compositions for oral administration aresolid or liquid and can take the form of capsules, tablets, coatedtablets, suspensions, etc., such carriers or excipients convenientlyused in the pharmaceutical art. Suitable tablet-ing excipien-ts includelactose, potato and maize starches, talc, gelatin and stearic andsilicic acids, magnesium stearate and polyvinyl pyrrolidone.

'For parenteral administration, the carrier or excipient can be asterile, parenterally acceptable liquids, e.g., Water, or aparen-terally acceptable oil, e.g., arachis oil, contained in ampoules.

In compositions for rectal administration, the carrier can comprise asuppository base, e.g., cocoa butter, or a glyceride.

A-dvantage'ously, the compositions are formulated as dosage units, eachunit being adapted to supply a fixed dose of active ingredient. Tablets,coated tablets, capsules, ampoules and suppositories are examples ofpreferred dosage unit forms according to the invention. Each dosage unitadapted for oral administration may conveniently contain 25 to 900 mg.,and preferably 100 to 500 mg, of the active ingredient; each dosage unitadapted for intracardial, intravenous, or inhalation administration mayconveniently contain 10 to 280 mg., and preferably 50 to 200 mg. of theactive ingredient; whereas each dosage unit adapted for intramuscularadministration may conveniently contain 20 to 400 mg. and preferably to3 00mg. of the active ingredient.

Examples of compositions within the preferred ranges given are asfollows:

(1) Dissolve 6 and 7 in hot water.

(2) This solution, when cool, is mixed with #3 and the mixture isstirred until uniform.

(3) Dissolve l, 2, 4, 5 and 8 in this solution and stir until uniform.

CAPSULES Ingredients: Per cap., mg. 1Active ingredient 250.000 2L-actose1146.000

3-Magnesium ste'arate 4.000

Procedure (1) Blend 1, 2 and 3. 2) Mill this blend and blend again.

(3) This milled blend is then filled into #1 hard gelatin capsules.

TABLETS Ingredients: Mg./tab., mg. 1--Active ingredient 200.0 2Cornstarch 20.0 3Kelacid 20.0 4Keltose 20.0 5-Magnesium stearate 1.3

Procedure (1) Blend 1, 2, 3, and 4.

(2) Add sufiicient water portionwise to the blend from step #1 withcareful stirring after each addition. Such additions of Water andstirring continue until the mass is of a consistency to permit itsconversion to wet granules.

(3) The wet mass is converted to granules by passing it through theoscillating granulator, using 8-mesh screen.

(4) The wet granules are then dried in an oven at F.

(5) The dried granules are then passed through an oscillatinggranulator, using a IO-mesh screen.

(6) Lubricate the dry granules with 0.5% magnesium stearate.

(7) The lubricated granules are compressed on a suitable tablet press.

INTRAVENOUS INJECTION Ingredients:

1-Active ingredient mg 50.0 2pH 4.0 buffer solution, q.s. to ml 1.0

Procedure (4) The ampoules are sealed under aseptic conditions.

INTRAMUSCULAR INJECTION Ingredients:

1Active ingredient mg 50.0 2Isotonic buffer solution 4.0, q.s. to ml 2.0

Procedure (1) Dissolve the active ingredient in the buffer solution.

(2) Aseptically filter the solution from Step #1.

(3) The sterile solution is now aseptically filled into sterileampoules.

(4)The ampoules are sealed under aseptic conditions.

SUPPOSITORIES Ingredients: For supp., mg. 1Active ingredient 200.02Polyethylene glycol 1000 1350.0 3-Polyethylene glycol 4000 450.0

Procedure (1) Melt 2 and 3 together and stir until uniform.

(2) Dissolve #1 in the molten mass from Step 1 and stir until uniform.

(3) Pour the molten mass from Step 2 into suppository molds and chill.

(4) Remove the suppositories from molds and wrap.

INHALATION Ingredients:

1Active ingredient mg 100 2Alcohol 95%, q.s. cc 1.0

Procedure mula:

Iii! N 1 (l N R wherein R is a member selected from the group consistingof hydrogen, lower alkyl, aryl, aralkyl and alicyclyl; R is a memberselected from the group consisting cf hydrogen and lower alkyl; R" is amember selected from the group consisting of hydrogen, halogen having anatomic weight less than 80, trifluoromethyl, lower alkyl and loweralkoxy; wherein m is -2 and n is 04, wherein aryl has a maximum of 12carbon atoms and a phenyl ring with substituents selected from the groupconsisting of hydrogen, trifiuoromethyl, halogen having an atomic weightless than 80, wherein aralkyl has a phenyl-lower alkyl radical and amaximum of nine carbon atoms,

wherein alicyclyl has a saturated ring having from four to seven carbonatoms and a maximum of nine carbon atoms and acid addition andquaternary ammonium salts thereof and (2) a pharmaceutical carrier.

2. A composition as defined in claim 1 wherein said antiarrhythmic agentis a hydrohalide salt of N-(l-cyclohexyl-3 -pyrrolidinyl) phthalimide.

3. A composition as defined in claim 1 wherein said antiarrhythmic agentis N-(1-cyclohexyl-3-pyrrolidinyl)- phthalimide hydrochloride.

4. A method of controlling cardiac arrhythmias in a living animal bodywhich comprises administering to said living animal body anantiarrhythmic amount of an agent selected from the group having thefollowing structural formula:

wherein R is a member selected from the group consisting of hydrogen,lower alkyl, aryl, aralkyl and alicyclyl; R is a member selected fromthe group consisting of hydrogen and lower alkyl; R is a member selectedfrom the group consisting of hydrogen, halogen having an atomic weightless than 80, trifiuoromethyl, lower alkyl and lower alkoxy; wherein mis 0-2 and n is 0-4, wherein aryl has a maximum of 12 carbon atoms and aphenyl ring with substituents selected from the group consisting ofhydrogen, trifluoromethyl, halogen having an atomic weight less than 80,wherein aralkyl has a phenyl-lower alkyl radical and a maximum of ninecarbon atoms, wherein alicyclyl has a saturated ring having from four toseven carbon atoms and a maximum of nine carbon atoms and acid additionand quaternary ammonium salts thereof,

5. A method of controlling cardiac arrhythmias as defined in claim 4wherein said R is cyclohexyl, R is hydrogen and R" is hydrogen.

6. A method of controlling cardiac arrhythmias as defined in claim 4wherein said R is cyclohexyl, R is hydrogen aud R" is chlorine.

7. A method of controlling cardiac arrhythmias which comprisesadministering to a living animal body an antiarrhythmic amount of acomposition comprising (1) an effective amount of a hydrohalide salt ofN-( l-cyclohexyl- 3-pyrrolidinyl)phthalimide and (2) a pharmaceuticalcarrier.

8. A method of controlling cardiac arrhythmias which comprisesadministering to a living animal body an antiarrhythmic amount of acomposition comprising (1) an effective amount ofN-(1-cyclohexyl-3-pyrrolidinyl)- phthalimide hydrochloride and (2) apharmaceutical carrler.

References Cited UNITED STATES PATENTS 3,137,705 6/1964 Prelog et al.260326 3,201,472 8/1965 Spivack 260326 ALBERT T. MEYERS, PrimaryExaminer.

H. M. ELLIS, Assistant Examiner.

